Parkinson's disease (PD) is the second most common neurodegenerative disorder afflicting 1.5 million individuals in the US and 6.3 million worldwide. The incidence of PD is expected to double by the year 2040. In the US, 50,000 new cases are diagnosed per year, and 1% of the population over the age of 55 is afflicted. The annual societal cost of PD is above $25 billion in the US alone.
The most common treatment for PD is 3,4-dihydroxyphenylalanine (levodopa or L-DOPA). While it remains the most effective therapy for the motor disability caused by PD, the vast majority of patients suffering from PD eventually develop a side effect characterized by abnormal involuntary movements known as L-DOPA induced dyskinesias (LID), which substantially compounds patient disability. Thus, LID is a common, devastating complication of the most efficacious therapeutic agent for PD. Dyskinesia is a disorder characterized by the presence of involuntary movements that are often uncontrollable. These movements are often choreiform (dance-like) in appearance but can also be more jerky and abrupt. They can affect any body parts including the arms and legs, muscles of the torso, chest, pelvis, face, lips, tongue, eyelids, and neck. It can even affect respiratory muscles. Some of these movements can be strong and violent that can lead to injuries including to the cervical spine (neck). Thus, dyskinesia is a major source of disability. Therefore, although L-DOPA is the gold standard in the management of PD, long-term treatment with L-DOPA is problematic. L-DOPA-induced dyskinesia affects 50% of treated PD patients by 5 years, and >90% by 10 years, which translates to an increase of approximately 10% per year. There are approximately 200,000 cases of LID in the US alone. Currently, amantadine (1-adamantanamine hydrochloride) is the only drug available that can modestly reduce LID, representing a deficient treatment with significant side effects of its own. Amantadine has an anti-dyskinetic effect likely due to its NMDA glutamate receptor antagonism, and it remains the only marketed agent with such a property. Several other experimental compounds targeting various transmitter systems have been tested, all with negative clinical trial outcomes. Moreover, in PD patients, LID is the main indication for the invasive and costly brain surgery known as Deep Brain Stimulation (DBS), an extreme option with the potential for serious neuropsychiatric side effects as well as the usual risks associated with invasive brain surgery. As a result, many patients are deemed poor candidates for this surgery, leaving their LID inadequately controlled.
Opioid Receptors and LID
Central to the development of LID appear to be changes in neuronal networks that are modulated by glutamatergic, adenosinergic, adrenergic, dopaminergic, serotoninergic, endocannabinoid and opioid mediated neurotransmission, all of which have been characterized to be altered in disease. Of these, opioid receptor mediated neurotransmission is of particular interest as opioids are co-transmitters that modulate basal ganglia function. Through this action, opioid drugs may help blunt the negative effects of pulsatile stimulation with L-DOPA therapy that is pathogenically related to LID. In LID, precursors of endogenous opioid receptor ligands are massively upregulated, with preproenkephalin levels increased in the striatum in animal models, as well as being observed in postmortem studies of patients. Additionally, enkephalin, dynorphin and alpha-neoendorphin are elevated significantly in the dyskinetic state, but not in normal or nondyskinetic Parkinsonian state. Therefore, it has been proposed that opioid receptor antagonism may be of benefit. However, the complexity of the basal ganglia circuitry, the presence of opioid receptors both pre- and post-synaptically, and on both excitatory and inhibitory neurons, significantly compound the intricacies of the response to opioid receptor ligands that must be considered. There are three major relevant classes of opioid receptors with differential distributions in the basal ganglia and with different functions:
Delta (δ)—Expressed predominantly in striatum and subthalamic nucleus, with lower levels in Globus Pallidus (GP) segments. These receptors regulate glutamate and acetylcholine release in the striatum.
Kappa (κ)—Expressed in all basal ganglia regions (striatum, GPe, GPi, STN, SN) & thalamus.
Mu (μ)—Expressed in all basal ganglia regions and thalamus.
Further complexity arises as expression of opioid receptors change in the Parkinsonian state. For example, kappa receptors are decreased in substantia nigra, and kappa and mu receptors are decreased in GPi in LID, likely secondary to alterations in opioid ligand expression. This complexity in distribution and function is probably the reason why non-selective antagonists have shown extremely varied efficacy in LID, worsening, not affecting, or ameliorating symptoms in animal models, and have not been effective in small clinical trials. Therefore, a level of specificity is believed to be required, but the precise nature of this specificity appears to be complex. The effects of more compounds can be summarized as follows:                The μ-opioid receptor selective antagonist cyprodime significantly reduces peak-dose LID. However, the selective μ-opioid receptor antagonist ADL5510 reduces LID but with a U-shaped dose response curve        The κ-opioid receptor selective agonist U50,488 reduces LID but worsens parkinsonism in MPTP-treated primates. However, the κ-opioid receptor selective antagonist nor-BNI moderates levodopa-induced hyperkinesias in the 6-hydroxydopamine-lesioned rat model.        Lower doses of the selective δ-opioid receptor antagonist naltrindole reduce levodopa-induced rotations in hemiparkinsonian marmoset monkeys.        Morphine (nonselective opioid receptor agonist) reduces dyskinetic movements in Parkinsonian primates and patients        Naloxone and Naltrexone (nonselective opioid receptor antagonists) have been tested with variable effects in monkeys and humans reporting no change, increases or decreases in LID.        

Collectively, the compounds tested to date indicate potential for modulating opioid receptors, but also indicate great complexity. Even those that are efficacious at some doses may display U-shaped dose response curves as non-specificity becomes an issue such as occurs with ADL5510. Consideration of these studies indicates that the most efficacious anti-dyskinetic agent acting on the opioid receptor system would have an as yet undiscovered mixture of pharmacological actions on different opioid receptors.
Safety Considerations of Opioid Drugs
Activation of opioid receptors is achieved by a number of widely used and abused opiates such as morphine and codeine. Despite the clear beneficial effects that these compounds can have in analgesia and other indications, they can have severe addictive and sedative effects, while antagonists can precipitate withdrawal symptoms in patients on opiates. Therefore, doses relevant for LID need to be considered in light of these side effects. The major specific side effects relevant to mu-antagonists are related to the gastrointestinal tract and dysphoria, while for kappa-agonists are sedation, worsening parkinsonism and dysphoria for example.
In summary, in LID there are increases in the release of opioid peptide precursors, therefore, modulation of opioid receptors is an attractive therapeutic approach. The complexity of how different opioid receptors regulate signaling at different sites within the circuitry of the basal ganglia dictates the selectivity profile that will be efficacious to modulate. The broad spectrum opioid receptor antagonists, such as Naloxone and Naltrexone, have been proposed as possible therapeutics, but have not been clinically successful. Selective agents for specific opioid receptor isoforms may offer limited benefits, but also demonstrate opposing dose-dependent effects that can substantially reduce their utility with significant dose-limiting adverse effects.
Thus, there remains a significant need for a therapeutic agent to treat L-DOPA-induced dyskinesias, since LID is a critical condition affecting a large and increasing population of PD patients. Further, there are other orphan diseases that exhibit dyskinesias for which treatments are unavailable or inadequate; these diseases include Huntington's disease, Tourette's syndrome and tardive dyskinesia. The present invention addresses these unmet needs.